Prior behavioral and pharmacological experience can markedly alter the behavioral effects of abused drugs. In many instances, these antecedent conditions can produce qualitative changes in the effect of drugs such as cocaine, amphetamine, chlordiazepoxide and morphine, with the result that these drugs produce effects that are opposite those normally found. The effects on these drugs that are not abused do not appear to be as malleable. For reasons that are presently unclear, prior history may contribute to the initial drug experience which may provide the basis for subsequent use and eventual substance abuse. The studies outlined in this proposal focus on an experimental evaluation of antecedent behavioral and pharmacological conditions that: i) alter the behavioral effects of cocaine and midazolam; ii) change the likelihood that these drugs will be self-administered; and iii) modify the subjective or discriminative stimulus effects of these drugs. Behavioral variables that will be examined include an analysis of the type of event, response class and contextual of concurrent environmental conditions. Pharmacological variables include previous experience with other drugs. Additional studies will determine whether changes in dopamine and/or serotonin to central receptor or transporter sites parallel modifications in drug effects produced by antecedent variables and might, in fact, mediate some of those effects. The studies outlined in this proposal will yield a better understanding of antecedent variables that enhance or impede an individual's vulnerability or predisposition to abuse drugs and will provide additional insight into the behavioral and pharmacological mechanisms contributing to those altered effects. Studies of this type may also become important for clarifying the etiology of drug abuse, as well as for implementing effective treatment and prevention strategies.